1. Field of the Invention
The present invention deals with defining a phytomedicinal water extract preparation of the plant species Uncaria. In this preparation, many of the ingredients leading to non-specific toxic side effects including palpability generated from the presence of such ubiquitous plant toxic compounds as polysacharrides and tannins are depleted (Cragg et al, Amer. Chem. Soc. Symposium Series 534:81-96, 1993). In addition, the most common biologically active plant products (e.g. steroids and alkaloids) are also depleted. This is accomplished by hot water extraction of the crude plant parts of Uncaria and subsequent dialysis of the solubilized products where a high degree of anti-tumor and immune stimulatory activities are maintained in the final dialyzed (low molecular weight) fraction.
2. Discussion of Related Art
Drugs derived from higher plants represent about 25% of all prescription drugs dispensed by pharmacies in the United States. For example, over 35,000 plant species have been screened between 1960 and 1986 for cytotoxic and antitumor properties which adds additional support to the concept that plant extracts are a potential rich source of medicines (Balandrin et al, Amer.Chem. Soc. Symposium Series 534:3-11, 1993). Most of the clinically useful plant products discovered so far have either been phytomedicines defined as ingested crude plant parts or as plant extract/tincture preparations (e.g. Gingo, Echinacea, Chamomile, St. John""s Wort, Saw Palmetto, Hawthorn, Lemon Balm), or as isolated chemical entities of two major chemical categoriesxe2x80x94namely the steroids and alkaloids (Balandrin et al, Amer. Chem. Soc. Symposium Series 534:3-11, 1993; V. E. Tyler, Amer.Chem. Soc. Symposium Series 534:24-38,1993).
There is prior art establishing that extracts of the plant species Uncaria contain alkaloids, sterols, and triterpenoids which in turn are known to possess antiviral, anti-inflammatory, anti-mutagenic and anti-tumor (cytotoxic) activities (K.Keplinger, PCT Int. Appl. WO 8210, 130,1985; Wagner et al, Planta Med. 419-23, Oct. 5, 1985; Senatore et al Boll.Ital. Biol. Sper. 65(5):517-20, 1989; Aquino et al, J. Nat. Prod. 52(4):679-85, 1989; Aquino et al, J. Nat. Prod. 53(3):559-64, 1990; Aquino et al, J. Nat. Prod. 54(2):453-9, 1991; Rizzi et al, J. Ethanopharmacol. 38(1):63-77, 1993). In fact, the available scientific literature teaches that the medicinal properties of the plant species Uncaria are due to the presence of these biologically active ingredients in phytomedicinal preparations of this plant. However, these components of Uncaria are usually extracted from the plant parts with organic solvents because of their poor solubility in water. It follows then that this prior art does not teach one skilled in the art that a low molecular weight, water soluble fraction of Uncaria would have any antitumor or immune stimulatory properties. Therefore, the discovery disclosed in this invention, that there is a high degree of biological activity in the hot water, low molecular weight fraction of Uncaria, is not obvious but novel and proprietary.
Phytomedicinal preparations of Uncaria (also known as Una de Gato and Cat""s Claw) have been sold in the United States and other countries for years as a herbal medicine. The basic formulation of these products has been encapsulated pulverized plant parts administered orally as 1-3 grams of crude bark per day. This method of preparation and dosing is a serious deviation from the historical medicinal use of Uncaria species described by the Indians indigenous to the Amazon basin of South America. Native Indians prepare treatments of Uncaria by drinking hot water extracts as a tea (1 cup or about 100 ml containing about 0.1-0.4 grams of crude plant parts per day). There is a 10-20 fold increase in the daily doses offered commercially compared to the practice of historical medicinal use. However, commercial Uncaria preparations rely on an efficient extraction and absorption of the active ingredients under the strong acidic conditions existing in the stomach. In contrast, the historical Uncaria medicinal preparations rely on hot water extracting the active components from the particulate fraction before they are ingested. There is no a priori scientific reason to believe that commercial preparations of Uncaria duplicate the historical practice of administering efficacious water-extracted doses to humans. For example, it is not obvious or taught by this prior art that acidic digestion of Uncaria crude plant parts in the stomach would even approximate the efficiency of hot water extraction. In addition, the hot water insoluble materials left behind when preparing tea extracts which are present in commercial crude plant part preparations, might cause stomach irritation, toxicity or limit the absorption of Uncaria""s active ingredients. It is significant that a recent review of the literature has revealed that there has never been a single peer-reviewed scientific article demonstrating any efficacious effects from human oral consumption of crude plant parts of Uncaria.
In one aspect, the present invention teaches that if the plant species of Uncaria are hot water extracted, which has been the practice from historical medicinal use, and then dialyzed to deplete ubiquitous non-specific toxic components and the levels of previously identified lipophilic components such as sterols and alkaloids possessing anti-tumor and anti-inflammatory properties, there still remains in the dialyzable fraction a novel phytomedicinal preparation of Uncaria having potent anti-tumor and immune stimulatory properties without any measurable toxic side effects. Any potential medicinal properties possessed by this subfractioned formulation of Uncaria would likely have been depleted of many of the known active ingredients of Uncaria, namely the sterols and alkaloids, because it is a low molecular weight water soluble preparation.
In another aspect, this invention discloses the method by which warm blooded animals could be treated successfully by oral administration of Uncaria water extracts. Here, it is disclosed that the water soluble portion of crude Uncaria bark at 3736 xcexcg of crude bark per ml (calculated from 198 xcexcg per milliliter dried water extract of C-Med-100, FIG. 1, Example 2 and the yield of C-Med-100 extract from crude bark=5.3%, Example 1) is necessary in order to inhibit 50% of tumor cell growth in vitro following a single dose. This would translate into a 70 kg person having to take 262 one gram capsules containing crude pulverized bark per day. It follows then that this invention permits the methodological advantage of delivering a safe and more efficacious in vivo treatment of Uncaria at doses 100 times higher than have ever been previously achieved with either commercial or historical preparations. Moreover, being water soluble, the new dialyzable fraction of Uncaria plant parts could be easily dried and combined with non-toxic inert carrier or diluent for convenient oral administration. Examples of such non-toxic, inert carriers include, but are not limited to, wheat starch and sodium carboxymethyl cellulose.